Intranasal administration of ketamine to treat depression

ABSTRACT

Methods and compositions for the treatment of treatment-resistant depression are described. More specifically, the invention demonstrates that intranasal administration of ketamine is effective to ameliorate the symptoms of depression in a patient who has not responded to an adequate trial of one antidepressant in the current episode and has recurrent or chronic depressive symptoms (&gt;2 years).

The present application is a continuation of U.S. patent applicationSer. No. 11/688,603 filed Mar. 20, 2007 which claims the priority ofU.S. Provisional Application No. 60/785,108 filed Mar. 22, 2006. Both ofwhich are incorporated by reference herein in their entirety.

This invention was made with government support under Grant No. MH002857awarded by the National Institutes of Health. The government has certainrights in the invention.

FIELD OF THE INVENTION

The present invention relates to methods and compositions for thetreatment of depression. More particularly, the invention relates tointranasal, intravenous and transdermal administration of ketamine totreat treatment-resistant depression.

BACKGROUND OF THE INVENTION

Depression is among the most disabling of all medical disorders with alifetime prevalence of approximately 17% [1]. It frequently appearsearly in life, can run a chronic course, and adversely affect theprognosis of other medical illnesses, such as coronary vascular disease,diabetes, and osteoporosis.

Depression is characterized by depressed mood, and markedly diminishedinterest or pleasure in activities. Other symptoms include significantweight loss or weight gain, decrease or increase in appetite, insomniaor hypersomnia, psychomotor agitation or retardation, fatigue or loss ofenergy, feelings of worthlessness or excessive or inappropriate guilt,diminished ability to think or concentrate or indecisiveness, recurrentthoughts of death, suicidal ideation or suicidal attempts. A variety ofsomatic symptoms may also be present. Though depressive feelings arecommon, especially after experiencing setbacks in life, depressivedisorder is diagnosed only when the symptoms reach a threshold and lastat least two weeks. Depression can vary in severity from mild to verysevere. It is most often episodic but can be recurrent or chronic. Somepeople have only a single episode, with a full return to premorbidfunction. However, more than 50 percent of those who initially suffer asingle major depressive episode eventually develop another.

Depression is more common in women than in men. The point prevalence ofunipolar depressive episodes is estimated to be 1.9% for men and 3.2%for women, and 5.8% of men and 9.5% of women will experience adepressive episode in a 12-month period. These prevalence figures varyacross populations and may be higher in some populations. A World HealthOrganization study has reported that depression is the leading globalcause of years of life lived with disability and the fourth leadingcause of disability-adjusted life-years. Disability-adjusted life-yearsrefers to the reduction in an individual's productive life, and is ameasure that takes into account premature mortality [2].

The treatment of depression was revolutionized about a half-century agoby the serendipitous discovery of monoamine oxidase inhibitors andtricyclic antidepressants. Since then, the availability of a host ofnewer medications with better side effect profiles has greatly increasedour ability to safely treat a significant percentage of patients.However, the newer medications are largely drugs that merely augment orotherwise potentiate the effects of the existing drugs by exerting theirprimary biochemical effects by increasing the intrasynaptic levels ofmonoamines.

Unfortunately, current medications for the treatment of depression takeweeks to months to achieve their full effects and in the meantime,patients continue to suffer from their symptoms and continue to be atrisk of self-harm as well as harm to their personal and professionallives. Indeed, the lag period of onset of action of several weeks oftraditional antidepressants is recognized as a major limitation,resulting in considerable morbidity and high risk of suicidal behaviorespecially in the first 9 days of starting antidepressants [3].Pharmacological strategies that have rapid onset of antidepressanteffects within hours or a few days and that are sustained wouldtherefore have an enormous impact on public health.

Recently, an “initiation and adaptation” paradigm for understanding thedelayed therapeutic actions of antidepressants has been proposed [4].This paradigm posits that the effect of acute drug administration ismediated via an initial direct target protein perturbation (e.g. bindingto a monoamine transporter, thereby resulting in monoamine reuptakeinhibition); with repeated administration, the same initial event, overtime, leads to enduring adaptive changes in critical neuronal networks,thereby resulting in stable long-term antidepressant effects. Thus, thisparadigm posits that the delay in the therapeutic actions of existingpharmacologic agents is due to the fact that they initially act onproteins, which are considerably upstream of the target genes, which areultimately responsible for the antidepressant effects. In this context,the major systems that have been postulated to mediate the delayedadaptive effects of antidepressants are neurotrophic signaling cascadesand the glutamatergic system [5].

The actions of antidepressants on neurotrophic signaling cascades hasbeen discussed by a number of groups [6-8]. The context of the presentapplication is with respect to the role of the glutamatergic system,most notably the NMDA system, in the actions of antidepressants [9-11],reviewed in [12]. NMDA receptor antagonists have antidepressant effectsin many animal models of depression, including the application ofinescapable stressors, forced-swim, and tail suspension-inducedimmobility tests, in learned helplessness models of depression, and inanimals exposed to a chronic mild stress procedure [13-18]. A singledose of the NMDA antagonist ketamine in male Wistar rats interferes withthe induction of behavioral despair for up to 10 days after itsadministration [19]. Additionally, repeated administration of differentclasses of antidepressants—in a time frame consistent with the delayedtherapeutic effects—brings about alterations in the expression of NMDAsubunit mRNA [20] and radioligand binding to these receptors in regionsof the brain implicated in the pathophysiology of depression [9].

Several lines of evidence also suggests that dysfunction of theglutamatergic system may play an important role in the pathophysiologyof depression [reviewed in 21, 22]. Notably, a recent study by Sanacoraet al. showed glutamate levels in the occipital cortex to besignificantly elevated, in 29 medication-free subjects with unipolarmajor depression, as compared to 28 age- and gender-matched healthycontrols [23]. Together, these data support the hypothesis of regionalalterations in glutamatergic signaling in mood disorders. Finally, inclinical trials, the glutamatergic modulators lamotrigine and riluzole(both inhibitors of glutamate release) were found to have antidepressantproperties [24-26].

Ketamine has been used in the treatment of breakthrough pain (BTP) inchronic pain patients. In such patients, 10-50 mg of ketamine has beenadministered through intranasal administration in incremental 10 mgdoses, every 90 seconds. The effect of that intranasal administration ofketamine was that there was a lower BTP in patients that receivedintranasal ketamine as opposed to placebo. There were very few sideeffects with such administration [47].

Transdermal administration of ketamine has also been used for thetreatment of intractable neuropathic pain [87]. Results indicated thatsubjects given a dose of 75 mg showed significant improvement in paindisability, and subjective physical and mental function. Azevedo et al.[88] report the results of a randomized, double-blind,placebo-controlled trial using racemic ketamine in a transdermaldelivery system after minor abdominal gynecological surgery usinglidocaine epidural blockade. At the end of the surgical procedure, acontrolled delivery transdermal patch containing either ketamine (25mg/24 hours) or placebo was applied. The time to rescue analgesic waslonger in the ketamine group (230±112 minutes) compared to the placebogroup (94±54 minutes).

The limitations in sustaining disorder remission are increasinglyapparent for standard treatments of treatment-resistant depression. Thefirst phase of the STAR*D study, the largest effectiveness study of itskind in “real world” patients, measured the efficacy of a SSRI,citalopram, in outpatients with depression (n=2,876). Remission rateswere 28%, a similar remission rate to that achieved in standardrandomized placebo-controlled acute efficacy trials [48]. As thepresence of residual symptoms is a strong predictor of relapse orrecurrence [49], therapeutic strategies going forward require a focus onachieving and sustaining remission, by presumably addressing corepathophysiological processes. Thus, it is evident that new methods areneeded for the treatment of chronic major depression that is resistantto treatment.

SUMMARY OF THE INVENTION

Methods and compositions for the treatment of treatment-resistantdepression are described. More specifically, the invention demonstratesthat intranasal administration of ketamine is effective to amelioratethe symptoms of treatment-resistant depression. In particularembodiments, the invention thus provides a method of treating a humanpatient for treatment-resistant depression, comprising intranasallyadministering a composition comprising ketamine to the patient at adosage sufficient to reduce or eliminate the symptoms of thetreatment-resistant depression. In more specific embodiments, theketamine is in a pharmaceutically acceptable carrier and is administeredat a dose of between about 0.1 mg/kg per day to about 3.0 mg/kg/day.

In specific embodiments, the symptoms of the treatment-resistantdepression are alleviated within 2 hours of intranasal administration ofthe ketamine.

The methods of the invention may be achieved through a method thatcomprises intranasal administration of a single dose of the ketamine.Alternatively, multiple doses of ketamine may be administered. Inspecific embodiments, a single intranasal administration of the ketamineis sufficient to alleviate the effects of the depression for 7 days, andin some cases, longer.

In other aspects of the invention, the method may further compriseadministering a pharmaceutically effective dose of a second agent,wherein the second agent is an antidepressant agent. The additionalagent may be any addition antidepressant agent. Exemplary suchantidepressant agents include but are not limited to at least one memberof lithium, a pharmaceutical antidepressant, an herbal antidepressant,an anticonvulsant, a mood stabilizer, an antipsychotic agent, and abenzodiazepine.

Also contemplated herein is a kit comprising a carrier for delivering aketamine intranasally containing in close confinement therein one ormore components, wherein: a) a first component contains ketamine; and b)a second component contains a psychotropic medication useful in thetreatment of depression. In a further aspect of the invention, thesecond component is selected from the group consisting of lithium,pharmaceutical antidepressant, an herbal antidepressant, ananticonvulsant, a mood stabilizer, an antipsychotic agent, and abenzodiazepine.

Also provided in the present invention is a device for patientself-administration of ketamine comprising a nasal spray inhalercontaining an aerosol spray formulation of ketamine and apharmaceutically acceptable dispersant, wherein the device is metered todisperse an amount of the aerosol formulation by forming a spray thatcontains a dose of ketamine effective to alleviate depression but whichdose of ketamine is determined by a physician or medical care providerto be below a level that causes dysphoria or psychosis.

In alternative embodiments, intravenous and transdermal administrationof ketamine are contemplated. In one alternative embodiment, theinvention thus provides a method of treating a human patient fortreatment-resistant depression, comprising intravenously administering acomposition comprising ketamine to the patient at a dosage sufficient toreduce or eliminate the symptoms of the treatment-resistant depression.In another alternative embodiment, the invention thus provides a methodof treating a human patient for treatment-resistant depression,comprising transdermally administering a composition comprising ketamineto the patient at a dosage sufficient to reduce or eliminate thesymptoms of the treatment-resistant depression. In more specificembodiments, the ketamine is in a pharmaceutically acceptable carrierand is administered at a dose of between about 0.1 mg/kg per day toabout 3.0 mg/kg/day.

In specific embodiments, the symptoms of the treatment-resistantdepression are alleviated within 2 hours of administration of theketamine.

The methods of the invention may be achieved through a method thatcomprises intravenous or transdermal administration of multiple doses ofthe ketamine. In specific embodiments, the ketamine is administered atleast two, at least three, at least four, at least five, at least six,at least seven, at least eight, at least nine times in fourteen days. Inother embodiments, the ketamine is administered at least two, at leastthree, at least four, at least five, at least six, at least seven, atleast eight, at least nine times in twenty-one days.

In other aspects of the invention, the method may further compriseadministering a pharmaceutically effective dose of a second agent,wherein the second agent is an antidepressant agent. The additionalagent may be any addition antidepressant agent. Exemplary suchantidepressant agents include but are not limited to at least one memberof lithium, a pharmaceutical antidepressant, an herbal antidepressant,an anticonvulsant, a mood stabilizer, an antipsychotic agent, and abenzodiazepine.

Also provided in the present invention is a device for patientself-administration of ketamine comprising a transdermal patchcontaining a formulation of ketamine and a pharmaceutically acceptablecarrier, wherein the device is metered to disperse an amount of theformulation that contains a dose of ketamine effective to alleviatedepression but which dose of ketamine is determined by a physician ormedical care provider to be below a level that causes dysphoria.

Other features and advantages of the invention will become apparent fromthe following detailed description. It should be understood, however,that the detailed description and the specific examples, whileindicating preferred embodiments of the invention, are given by way ofillustration only, because various changes and modifications within thespirit and scope of the invention will become apparent to those skilledin the art from this detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

The following drawings form part of the present specification and areincluded to further illustrate aspects of the present invention. Theinvention may be better understood by reference to the drawings incombination with the detailed description of the specific embodimentspresented herein.

FIG. 1 Enrollment, randomization, withdrawals and completion of the twotreatment phases (n=18)

FIG. 2 Change in 21 HDRS, BPRS positive symptoms and YMRS scores overone week (n=18). Abbreviations: BPRS Brief Psychiatric Rating Scale;HDRS: Hamilton Depression Rating Scale; YMRS: Young Mania Rating Scale.

FIG. 3A Portion of responders (50% improvement on HDRS) to ketamine andplacebo from minute 40 to day 7 post-infusion (n=18).

FIG. 3B Portion of remitters (HDRS≦7) to ketamine and placebo fromminute 40 to day 7 post-infusion (n=18).

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS OF THE INVENTION

Existing therapies for major depression have a lag of onset of action ofseveral weeks, resulting in considerable morbidity and high risk ofsuicidal behavior. Exploring pharmacological strategies that have rapidonset of antidepressant effects within a few days and that are sustainedwould have an enormous impact on patient care. Converging lines ofevidence suggest the role of the glutamatergic system in thepathophysiology and treatment of mood disorders.

Based on the preclinical and preliminary clinical studies, the inventorspostulated that the NMDA receptor complex may mediate the delayedtherapeutic effects of traditional monoaminergic based antidepressants,and furthermore that directly targeting the NMDA receptor would bringabout rapid antidepressant effects. Indeed, in a preliminary study of 7subjects with major depression, it was reported that a singleintravenous dose of the high-affinity NMDA receptor antagonist ketamineresulted in a rapid and short-lived antidepressant effect [27]. In thepresent invention, the inventors have performed studies to determine ifketamine does indeed exert rapid antidepressant effects in a relativelyrefractory population, and furthermore, if these effects of a singledose of ketamine are sustained.

The exemplary data provided herein were obtained from a randomized,placebo-controlled, double-blind crossover study on patients that hadDSM-TV (Diagnostic and Statistical Manual of Mental Disorders, fourthedition; DSM-IV) treatment-resistant major depression. The term“treatment-resistant major depression” refers to the depressionexperienced by any subject who has not previously responded to twoadequate antidepressant trials (adequacy of antidepressant trials weredetermined with the Antidepressant Treatment History Form).Treatment-resistant major depression is a relatively common occurrencein clinical practice, with up to 50 to 60% of patients not achievingadequate response following antidepressant treatment [52]. At a minimum,treatment resistant-depression includes unipolar depression that doesnot respond satisfactorily to one or more treatments that are optimallydelivered [53]. If the depression has not benefited from at least twoadequate trials of medications from different classes in the currentepisode, clinically significant resistance is present [54]. Severalschemes to “stage” the degree of resistance have been proposed. The mostwidely accepted scheme uses the staging system of Thase and Rush [55].The stages of resistance are as follows:

Stage I: Failure of at least one adequate trial of one major class ofantidepressant;

Stage II: Stage I resistance plus failure of adequate trial of anantidepressant in a distinctly different class from that used in Stage I

Stage III: Stage II resistance plus failure of an adequate trial of aTCA

Stage IV: Stage III resistance plus failure of an adequate trial of aMAOI

Stage V: Stage IV resistance plus failure of a course of bilateral ECT

Thus, from the above schemes, the skilled person may understandtreatment-resistant depression patients to include patients that havefailed to respond to one adequate trial of an antidepressant (Stage I).

Another staging system takes into consideration both the number offailed trials as well as the intensity/optimization of each trial, anddoes not make assumptions regarding a hierarchy of antidepressantclasses. Massachusetts General Hospital (MGH) Staging Method to ClassifyTreatment-Resistant Depression:

(1) Non-response to each adequate (at least 6 weeks of an adequate doseof antidepressant) trial of a marketed antidepressant generates anoverall score of resistance (1 point per trial);

(2) Optimization of dose, optimization of duration, andaugmentation/combination of each trial (based on the MGH orAntidepressant Treatment Response Questionnaire) increase the overallscore (0.5 point per trial per optimization/strategy);

(3) ECT increases the overall score by 3 points ECT, electroconvulsivetherapy.

Finally, many researchers use the guidelines proposed by theAntidepressant Treatment History Form (ATHF, Sackeim 2001,Neuropsychopharmacology 25: 713-728). The Antidepressant TreatmentHistory Form defines the adequacy of the treatment on a continuum forboth dose and duration, providing categories rated 0 through 4. The ATHFprovides for different levels of resistance. A level 3 degree ofresistance for fluoxetine, for example, requires at least 4 weeks offluoxetine at at least 20 mg/day. Although they are somewhat arbitrary,these benchmarks do reflect reasonable clinical distinctions amongprevious treatment trials. Validation of this approach has been achievedfor acute phase treatment response to electroconvulsive therapy (ECT)and vagus nerve stimulation (VNS).

Thus, the patient population to be treated by the present invention maybe defined according to any one or more of the above schemes. After a2-week drug-free period, exemplary subjects having treatment-resistantdepression were given an intravenous infusion of either ketaminehydrochloride (0.5 mg/kg) or placebo on 2 test days, a week apart.Subjects were rated at baseline and at 40, 80 minutes, 110 minutes, 230minutes and days 1, 2, 3 and 7 post-infusion. The outcome of thetreatment was measured using changes in scores on the primary efficacyto measure the 21-item Hamilton Depression Rating Scale (HDRS). Fromthese studies it was shown that subjects on ketamine showed significantimprovement in depression compared to placebo within 110 minutes afterinjection that remained significant throughout the following week. Theeffect size for the drug difference was very large (d=1.46, 95% C.I.0.91-2.01) after 24 hours and moderate to large (d=0.68, 95% C.I.0.13-1.23)) after 1 week. Of the subjects treated with ketamine, 71% metresponse and 29% met remission criteria the day following ketamineinfusion. Thirty-five percent of subjects maintained response for atleast 1 week. From these data it can be concluded that robust and rapidantidepressant effects can result from a single intravenous dose of anNMDA antagonist; onset of improvement was evident within 2 hourspost-infusion and continued to remain significant for 1 week.

The present invention is directed to methods and compositions fortreating treatment-resistant depression using intranasal administrationof ketamine. Such a treatment may be administered alone or may besupplemented with other antidepressant therapies as described below.

Intravenous administration of ketamine also has been used for thetreatment of treatment-resistant major depression. In that study, a 0.5mg/kg intravenous infusion was given over 40 minutes. Improvements indepression were seen within 2 hours post-injection; and continued for upto 1 week. There were no serious adverse events; ceased within 80 minpost-infusion (euphoria, elevated BP, increased libido, perceptualdisturbances; Zarate et al, 2006).

Intranasal (IN) ketamine plasma levels used for pain is 3-4 fold lowerthan the intravenous (IV) ketamine studies in depression [27, 78-86].The slow infusion of ketamine produces gradually increasing plasmalevels during the infusion period. Dose-wise, the typical ketamine dosefor surgical induction is between 1.0-2.0 mg/kg, with additionalketamine used to sustain anesthesia. In anesthesia, the target ketamineblood level is reached with ketamine bolus doses between 0.2-0.26 mg/kgover 1 min, so the dose for anesthesia is around 5 times less than theIV dose. The dose for ketamine plasma levels to produce antidepressantresponses as opposed to the levels needed to produce anesthesia is inthe range of 0.5 mg/kg over 40 min. The reports of dissociation in theCan study and other pain studies were significantly lower than the IVstudies in MDD because the ketamine levels achieved intranasally inthese studies were much lower. The intranasal dose used for pain (50 mg)is roughly equivalent to 0.1 mg/kg i.v. of ketamine.

In the present invention, the methods described are for the treatment ofdepression in which up to 50 mg of ketamine is administeredintranasally. Such an administration may be administered over a 1 hourtime period or more or less. As depression is a chronic illnessrequiring maintenance treatment, it is expected that chronicadministration of the intranasal formulation may be employed asnecessary, ranging from daily to weekly, depending on response. Shouldthe 50 mg IN dosage prove to be inadequate to treat depressioneffectively increasing doses, e.g., approximately 100 mg, approximately150 mg, approximately 200 mg, approximately 250 mg total ketamine willbe administered intranasally, to establish the relative equivalent ofthe 0.5 mg/kg dosage usage in the TV studies.

The intranasal administration of ketamine will be well tolerated at thedosage used. In terms of efficacy, it is contemplated that the positiveresults seen with treatment of depression using an IV route ofadministration will be observed with the intranasal.

In some embodiments, the intranasal ketamine formulation will be usedfor an outpatient group of depressed patients who are consideredtreatment-resistant. The intranasal formulation will eliminate thenecessity of patient presentation to a hospital or clinic forintravenous administration. The patient can take intranasal ketamine intheir own home, with no need for a needle stick. Thus, the acceptabilityof the treatment for patients will be better than with the TV ketamine.The patient may be one that is at least a moderately treatment-resistantpatient, who is seeking new options for the rapid and safe reduction ofdepressive symptoms. The physician would monitor the patient as anoutpatient, and could adjust dosage as they would for an orallyadministered medication.

Ketamine ((2-(2-chlorophenyl)-2-(methylamino)-cyclohexanone) is ageneral anesthetic used by anesthesiologists, veterinarians, andresearchers. Nasal administration of ketamine and midazolam to achievesedation for ophthalmic surgery, and to induce anesthesia prior toelective surgery in healthy children has been reported [50, 51].Usually, ketamine is administered intramuscularly (i.m.) orintravenously (i.v.) to induce anesthesia. However, intranasalcompositions of ketamine are available from e.g., JavelinPharmaceuticals.

Ketamine has also been known to have analgesic properties [56];analgesia can be achieved with subanesthetic doses of ketamine[57, 58].The drug is administered by various routes, including i.v., i.m.,caudal, intrathecal, and subcutaneous (s.c.). Subcutaneousadministration of ketamine has been used to treat pain following surgeryand associated with terminal cancer [see, e.g., 59]. Ketaminehydrochloride administered via a subcutaneous cannula was reported tosuccessfully treat phantom limb pain [60].

As explained above, management of treatment-resistant depression iscomplex and frequently unsuccessful. In the present invention, it isshown that non-competitive N-methyl-D-aspartate (NMDA) receptorantagonists, such as ketamine, will form a first line defense againsttreatment-resistant depression if administered through the nasal route.

The present invention is broadly directed to a method for treatingtreatment-resistant depression. More particularly, the inventors havediscovered that administration via a nasal route of a dose of ketamineis effective to alleviate depression in patients suffering fromtreatment resistant depression. In a further embodiment, the presentinvention provides for pulmonary administration of ketamine byinhalation. Nasal administration of an anti-depressant dose of ketamineadvantageously allows for patient self administration of the drug, whichprovides for depression management on an outpatient basis. Moreover,ketamine administration in nasal sprays and inhalers are generallysocially acceptable.

Another advantage of the invention is that it allows the administrationof lesser amount of a second anti-depressant agent for the treatment oftreatment-resistant depression. As such, in some embodiments, theintranasal administration of the ketamine may have an additive effectwhen administered in combination with another antidepressant.

Ketamine is an inexpensive, readily available drug, with minor adverseside effects. Thus, the invention contemplates additional savings to theoverburdened health care system. Nasal administration of this agent israpid, allowing for fast action of the drug, and easily accomplished bya non-medically trained patient.

In one aspect, the depression-alleviating dose of ketamine isapproximately 0.01 to approximately 1 mg/kg of body weight. In a morepreferred aspect, the dose of ketamine is approximately 0.05 toapproximately 0.7 mg/kg of body weight. In another embodiment, the totaldose of ketamine per nasal administration ranges from about 1 to about250 mg.

In a specific aspect of the invention, the dose of ketamine is effectiveto alleviate depression in a patient suffering from treatment-resistantdepression. In a particular aspect, nasal administration of ketamine canbe a supplemental therapy in a depression management regimen thatinclude administration of one or more additional antidepressant agents.Such additional agents may be administered through a nasal route orthrough another route. The additional agents may be administeredconcurrently with the ketamine or before or after the ketamineadministration.

The ketamine may be provided in a metered dose which is well below thelevel associated with dysphoria or hallucination. In other aspects thedose of the second antidepressant agent is provided in an amounteffective to alleviate depression with the ketamine; preferably thesecond antidepressant agent is administered via the mucosal route withthe ketamine.

The invention provides a device for patient self-administration ofketamine, which device comprises a nasal inhaler containing an aerosolformulation of ketamine and a pharmaceutically acceptable dispersant,wherein the device is metered to disperse an amount of the aerosolformulation that contains a dose of ketamine effective to alleviatedepression. The dispersant may be a surfactant, such as, but not limitedto, polyoxyethylene fatty acid esters, polyoxyethylene fatty acidalcohols, and polyoxyethylene sorbitan fatty acid esters.Phospholipid-based surfactants also may be used.

In other embodiments, the aerosol formulation of ketamine is provided asa dry powder aerosol formulation in which the ketamine is present as afinely divided powder. The dry powder formulation can further comprise abulking agent, such as, but not limited to, lactose, sorbitol, sucroseand mannitol.

In another specific embodiment, the aerosol formulation is a liquidaerosol formulation further comprising a pharmaceutically acceptablediluent, such as, but not limited to, sterile water, saline, bufferedsaline and dextrose solution.

In further embodiments, the aerosol formulation further comprises asecond antidepressant agent in a concentration such that the meteredamount of the aerosol formulation dispersed by the device contains adose of the second agent in a metered amount that is effective toameliorate the symptoms of depression when used in combination with theketamine.

Thus, the invention provides a self administration method for outpatienttreatment of treatment-resistant depression. Such administration may beused in a hospital, in a medical office or outside a hospital or medicaloffice by non-medical personnel for nasal self administration ofketamine.

The present invention is based on the surprising and unexpecteddiscovery that nasal administration of ketamine can alleviate symptomsof chronic, treatment-resistant depression. Thus, patients that havepreviously been refractory to treatment with antidepressants, was ableto achieve more satisfactory depression management by nasaladministration of 8-32 mg of ketamine, corresponding to [0.13 to 0.53]mg/kg of body weight. However, it is contemplated that up to 250 mg ofketamine may be administered intranasally for the treatment ofdepression. In one preferred embodiment, a ketamine dosage of 0.5 mg/kgwas effective to improve mood at 40 minutes through 7 days in patientsthat previously manifested treatment-resistant depression. The inventionshows a robust and rapid (within hours of intranasal administration) andrelatively sustained (effects lasting 1 week) response to even asingle-dose of the NDMA antagonist ketamine. Notably, subjects treatedwith intranasal ketamine were better than placebo within 2 hours (110minutes) and remained better through 7 days. In addition, the inventionalso shows that IV administration of f ketamine can alleviate symptomsof chronic, treatment-resistant depression. Thus, patients that havepreviously been refractory to treatment with antidepressants, was ableto achieve more satisfactory depression management by IV administrationof ketamine. Again, subjects treated with IV ketamine were better thanplacebo within 2 hours (110 minutes) and remained better through 7 days.

Any chronic, treatment-resistant depression may be treated by themethods described herein. Such depression may include but is not limitedto any of: major depressive disorder, single episode, recurrent majordepressive disorder-unipolar depression, seasonal affectivedisorder-winter depression, bipolar mood disorder-bipolar depression,mood disorder due to a general medical condition-with majordepressive-like episode, or mood disorder due to a general medicalcondition-with depressive features, wherein those disorders areresistant to treatment in a given patient. Thus, any patient thatpresents one of those disorders and who has not responded to an adequatetrial of one antidepressant in the current episode and has recurrent orchronic depressive symptoms for greater than 2 years can be treated bythe methods of the invention. Manic Depressive illnesses are alsodescribed in Goodwin, et al., [61].

There are three types of depression generally characterized in the art,major depression, dysthymic disorder, or dysthymia, and depressivedisorder not otherwise specified. Major depression is characterized bypeak episodes of extreme depression. During a peak episode, the patientmay suffer from depressed mood, and markedly diminished interest orpleasure in activities. Other symptoms include significant weight lossor weight gain, decrease or increase in appetite, insomnia orhypersomnia, psychomotor agitation or retardation, fatigue or loss ofenergy, feelings of worthlessness or excessive or inappropriate guilt,diminished ability to think or concentrate or indecisiveness, recurrentthoughts of death, suicidal ideation or suicidal attempts. Symptoms lastfor at least two weeks and cause significant distressor impairment inimportant areas of functioning.

Dysthymia is characterized by depressed mood for at least 2 years aswell as other symptoms like poor appetite or overeating, insomnia orhypersomnia, low energy or fatigue, low self esteem, poor concentrationor difficulty making decisions and feelings of hopelessness. As isrecognized in the field of psychiatric arts, depression may alsocomprise, and/or may also manifest itself in a variety of forms,including but not limited to, seasonal affective disorder, diurnal moodvariations, or depression associated with menopause. Diagnostic criteriafor dysthymia and major depression, as well as for seasonal affectivedisorder, diurnal mood variations and depression associated withmenopause, are more fully explained in the Diagnostic and StatisticalManual of Mental Disorders, Fourth Edition, (DSM IV) published by theAmerican Psychiatric Association or by the ICD (ICD-10: InternationalStatistical Classification of Diseases and Related Health Problems (10thRevision) or any other psychiatric classification system.

Depression with seasonal affective pattern or seasonal affectivedisorder (hereinafter referred to as “SAD”) is also known as cabinfever, evening blues, and sun deprivation syndrome. The terms “seasonalaffective disorder” or “seasonal pattern specifier” are defined in theDSM-IV as a specifier or adjective that more precisely characterizefeature associated with depression. A particular feature of SAD is theregular occurrence of depression in winter.

Most of the patients with SAD are characterized by an atypical type ofdepression in the winter which is associated with mood reactivity (moodbrightens in response to actual or potential positive events) as well asweight gain or increase in appetite, hypersomnia, leaden paralysis(heavy, leaden feelings in arms or legs), long-standing pattern ofinterpersonal rejection sensitivity.

The diagnosis of depression usually follows a clinical evaluation by apsychiatrist or other mental health professionals. The two mostrecognized sets of diagnostic criteria for major depressive disorder andother depressive, or mood disorders, are outlined in the DSM, Diagnosticand Statistical Manual of Mental Disorders, Fourth Edition, (DSM IV)published by the American Psychiatric Association and the ICD (ICD-10:International Statistical Classification of Diseases and Related HealthProblems-10th Revision, published periodically by the World HealthOrganization) or any other psychiatric classification system.

The presence and the severity of the depressive state can also bedetermined with structured and semi-structured interview and questionerssuch as the Hamilton score that is well known in the art. [62].Accordingly, the present invention is directed of methods foralleviating treatment-resistant depression on an outpatient basis bynasal administration of ketamine, and to devices usable by non-medicalpersonnel for nasal self-administration of ketamine.

Ketamine will preferably be prepared in a formulation or pharmaceuticalcomposition appropriate for nasal administration. Suitable formulationsare discussed in detail, infra. In a further embodiment, ketamine can beformulated with a mucosal penetration enhancer to facilitate delivery ofthe drug. The formulation can also be prepared with pH optimized forsolubility, drug stability, absorption through nasal mucosa, and otherconsiderations.

The invention provides for administration of a therapeutically effectivedose of ketamine, i.e., a dose effective to alleviatetreatment-resistant depression. The actual dose will vary, depending onthe body weight of the patient, the severity of the depression, theroute of administration, the nature of medications administeredconcurrently, the number of doses to be administered per day, and otherfactors generally considered by the ordinary skilled physician in theadministration of drugs. In a specific embodiment, the amount ofketamine administered to a patient suffering from treatment-resistantdepression is about 10% to about 20% of the amount used to induceanesthesia. In another specific embodiment, the dose of ketamine isabout 0.01 mg per kg of body weight (0.01 mg/kg) to about 1 mg/kg;preferably about 0.05 mg/kg to about 0.7 mg/kg. In yet anotherembodiment, the dose ranges from about 1 mg to about 250 mg. A dose ofany integer between these two numbers is contemplated. Thus, forexample, intranasal, transdermal, intravenous, intradermal, orsubcutaneous formulations respectively containing total intranasal,transdermal, intravenous, intradermal, or subcutaneous doses of 1 mg, 2mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg,50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg,100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg,190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg are specificallycontemplated. Preferably, the effective dose is titrated under thesupervision of a physician or medical care provider, so that the optimumdose for the particular application is accurately determined. Thus, thepresent invention provides a dose suited to each individual patient.

Once the dosage range is established, a further advantage of theinvention is that the patient can administer ketamine on an as-needed,dose-to-effect basis. Thus, the frequency of administration is undercontrol of the patient. However, the relatively low dose with eachadministration will reduce the possibilities for abuse.

Yet another particular advantage of the present invention is that nasaladministration of ketamine is non-invasive, and provides forintroduction into the bloodstream almost as fast as i.v. administration,and much faster than perioral administration.

More importantly, a patient can control administration of theantidepressant medication, because nasal administration provides forprecise control over the dosage and effect of the drug used to offsetchanges in depression throughout an administration period. Nasaladministration of ketamine optimally provides for dose-to-effectadministration of the drug.

The term “nasal administration” in all its grammatical forms refers toadministration of a drug through the nasal mucous membrane to thebloodstream for systemic delivery of the drug. The advantages of nasaladministration for drug delivery are that it does not require injectionusing a syringe and needle, it avoids necrosis that can accompany i.m.administration of drugs, and trans-mucosal administration of a drug ishighly amenable to self administration.

The present invention contemplates pulmonary administration through aninhaler.

The ketamine may be formulated with a “mucosal penetration enhancer,”i.e., a reagent that increases the rate or facility of transmucosalpenetration of ketamine, such as but not limited to, a bile salt, fattyacid, surfactant or alcohol. In specific embodiments, the permeationenhancer can be sodium cholate, sodium dodecyl sulphate, sodiumdeoxycholate, taurodeoxycholate, sodium glycocholate, dimethylsulfoxideor ethanol.

A “therapeutically effective amount” of a drug is an amount effective todemonstrate a desired activity of the drug. According to the instantinvention, a therapeutically effective amount of ketamine is an amounteffective to alleviate, i.e., noticeably reduce, the symptoms oftreatment-resistant depression patient.

Those skilled in the art are well aware of nasal administration ofketamine for treating pain (see U.S. Pat. No. 5,543,4354, incorporatedherein by reference in its entirety) Through such nasal and pulmonaryadministration of ketamine and additional therapeutically active drugsor agents with which ketamine can be administered to treat depression asdiscussed herein.

The present invention contemplates formulations comprising ketamine foruse in a wide variety of devices that are designed for the delivery ofpharmaceutical compositions and therapeutic formulations to therespiratory tract, preferably the nasal passages. The preferred route ofadministration of the present invention is in an aerosol spray for nasalinhalation. Ketamine, combined with a dispersing agent, or dispersant,can be administered in an aerosol formulation as a dry powder or in asolution or suspension with a diluent.

As used herein, the term “aerosol” refers to suspension in the air. Inparticular, aerosol refers to the particlization or atomization of aformulation of the invention and its suspension in the air. According tothe present invention, an aerosol formulation is a formulationcomprising ketamine for nasal inhalation or pulmonary administration.

As used herein, the term “inhaler” refers both to devices for nasal andpulmonary administration of a drug, e.g., in solution, powder and thelike. For example, a the term “inhaler” is intended to encompass apropellant driven inhaler, such as is used for to administerantihistamine for acute asthma attacks, and plastic spray bottles, suchas are used to administer decongestants.

As used herein, the term “dispersant” refers to an agent that assistsaerosolization of the ketamine or absorption of the ketamine in mucosaltissue, or both. In a specific aspect, the dispersant can be a mucosalpenetration enhancer. Preferably, the dispersant is pharmaceuticallyacceptable. As used herein, the term “pharmaceutically acceptable” meansapproved by a regulatory agency of the Federal or a state government orlisted in the U.S. Pharmacopeia or other generally recognizedpharmacopeia for use in animals, and more particularly in humans.

Suitable dispersing agents are well known in the art, and include butare not limited to surfactants and the like. Such surfactants aregenerally used in the art to reduce surface induce aggregation ofketamine caused by atomization of the solution forming the liquidaerosol and may be used in the methods and devices of the presentinvention. Examples of such surfactants include, but are not limited to,surfactants such as polyoxyethylene fatty acid esters and alcohols, andpolyoxyethylene sorbitan fatty acid esters. Amounts of surfactants usedwill vary, being generally within the range or 0.001 and 4% by weight ofthe formulation. Suitable surfactants are well known in the art, and canbe selected on the basis of desired properties, depending on thespecific formulation, concentration of ketamine, diluent (in a liquidformulation) or form of powder (in a dry powder formulation), etc.

The liquid aerosol formulations contain ketamine and a dispersing agentin a physiologically acceptable diluent. The dry powder aerosolformulations of the present invention consist of a finely divided solidform of ketamine and a dispersing agent. With either the liquid or drypowder aerosol formulation, the formulation must be aerosolized. Thatis, it must be broken down into liquid or solid particles in order toensure that the aerosolized dose actually reaches the mucous membranesof the nasal passages or the lung. The term “aerosol particle” is usedherein to describe the liquid or solid particle suitable for nasal orpulmonary administration, i.e., that will reach the mucous membranes.Other considerations, such as construction of the delivery device,additional components in the formulation, and particle characteristicsare important. These aspects of nasal or pulmonary administration of adrug are well known in the art, and manipulation of formulations,aerosolization means and construction of a delivery device require atmost routine experimentation by one of ordinary skill in the art.

In a particular embodiment, the mass median dynamic diameter will be 5micrometers or less in order to ensure that the drug particles reach thelung alveoli (Wearley, L. L., 1991, 1991, Crit. Rev. in Ther. DrugCarrier Systems 8:333).

With regard to construction of the delivery device, any form ofaerosolization known in the art, including but not limited to spraybottles, nebulization, atomization or pump aerosolization of a liquidformulation, and aerosolization of a dry powder formulation, can be usedin the practice of the invention.

As noted above, in a preferred aspect of the invention, the device foraerosolization is a metered dose inhaler. A metered dose inhalerprovides a specific dosage when administered, rather than a variabledose depending on administration. Such a metered dose inhaler can beused with either a liquid or a dry powder aerosol formulation. Metereddose inhalers are well known in the art.

For nasal administration, a useful device is a small, hard bottle towhich a metered dose sprayer is attached. In one embodiment, the metereddose is delivered by drawing the ketamine solution into a chamber ofdefined volume, which chamber has an aperture dimensioned to aerosolizeand aerosol formulation by forming a spray when a liquid in the chamberis compressed. The chamber is compressed to administer the ketamine. Ina specific embodiment, the chamber is a piston arrangement. Such devicesare commercially available.

Alternatively, a plastic squeeze bottle with an aperture or openingdimensioned to aerosolize an aerosol formulation by forming a spray whensqueezed. The opening is usually found in the top of the bottle, and thetop is generally tapered to partially fit in the nasal passages forefficient administration of the aerosol formulation. Preferably, thenasal inhaler will provide a metered amount of the aerosol formulation,for administration of a measured dose of the drug.

Often, the aerosolization of a liquid or a dry powder formulation forinhalation into the lung will require a propellent. The propellent maybe any propellant generally used in the art. Specific nonlimitingexamples of such useful propellants are a chlorofluorocarbon, ahydrofluorocarbon, a hydrochlorofluorocarbon, or a hydrocarbon,including trifluoromethane, dichlorodifluoromethane,dichlorotetrafluoroethanol, and 1,1,1,2-tetrafluoroethane, orcombinations thereof.

Systems of aerosol delivery, such as the pressurized metered doseinhaler and the dry powder inhaler are disclosed in Newman, S. P.,Aerosols and the Lung, Clarke, S. W. and Davia, D. editors, pp. 197-22and can be used in connection with the present invention.

In general, the ketamine is introduced into the subject in the aerosolform in an amount between about 0.01 mg per kg body weight of the mammalup to about 1 mg per kg body weight of said mammal. In a specificembodiment, the dosage is administered as needed. One of ordinary skillin the art can readily determine a volume or weight of aerosolcorresponding to this dosage based on the concentration of ketamine inan aerosol formulation of the invention.

The present invention provides liquid aerosol formulations and dosageforms for use in treating subjects suffering from treatment-resistantdepression. In general such dosage forms contain ketamine in apharmaceutically acceptable diluent. Pharmaceutically acceptablediluents in such liquid aerosol formulations include but are not limitedto sterile water, saline, buffered saline, dextrose solution, and thelike. In a specific embodiment, a diluent that may be used in thepresent invention or the pharmaceutical formulation of the presentinvention is phosphate buffered saline or a buffered saline solutiongenerally between the pH 7.0-8.0 range, or water.

The liquid aerosol formulation also may optionally includepharmaceutically acceptable carriers, diluents, solubilizing oremulsifying agents, surfactants and excipients.

The formulation may include a carrier. The carrier is a macromoleculewhich is soluble in the circulatory system and which is physiologicallyacceptable where physiological acceptance means that those of skill inthe art would accept injection of said carrier into a patient as part ofa therapeutic regime. The carrier preferably is relatively stable in thecirculatory system with an acceptable plasma half life for clearance.Such macromolecules include but are not limited to Soya lecithin, oleicacid and sorbitan trioleate, with sorbitan trioleate preferred.

The formulations of the present embodiment may also include other agentsuseful for pH maintenance, solution stabilization, or for the regulationof osmotic pressure. Examples of the agents include but are not limitedto salts, such as sodium chloride, or potassium chloride, andcarbohydrates, such as glucose, galactose or mannose, and the like.

The present invention further contemplates liquid aerosol formulationscomprising ketamine and another therapeutically effective drug, such asa described in further detail below.

It is also contemplated that the present aerosol formulation can beprepared as a dry powder formulation comprising a finely divided powderform of ketamine and a dispersant. For example, the dry powderformulation can comprise a finely divided dry powder containingketamine, a dispersing agent and also a bulking agent. Bulking agentsuseful in conjunction with the present formulation include such agentsas lactose, sorbitol, sucrose, or mannitol, in amounts that facilitatethe dispersal of the powder from the device.

In a further embodiment, an aerosol formulation of the present inventioncan include other therapeutically or pharmacologically activeingredients in addition to ketamine, such as but not limited to aconventional antidepressant therapies that include, but are not limitedto: antidepressants: biogenic amine non-selective reuptake inhibitors,e.g., tricyclic antidepressants like Imipramine; serotonin selectivereuptake inhibitors like Fluoxetine (Prozac); monoamine oxidaseinhibitors (MAO-I) like phenelezine; other types of antidepressantmedications including atypical antidepressants. Antidepressantsaugmentation with other medications e.g., lithium, T3, T4, etc. Othertreatment modalities with antidepressant effects: electro-convulsivetreatment (ECT); light therapy psychotherapy e.g., cognitive orinterpersonal therapy for depression.

In addition, administration of drugs, reported to ameliorate orexacerbate the symptoms of a neuropsychiatric disorder, include but arenot limited to compounds include antidepressants such as lithium salts,carbamazepine, valproic acid, lysergic acid diethylamide (LSD),p-chlorophenylalanine, p-propyidopacetamide dithiocarbamate derivativese.g., FLA 63; anti-anxiety drugs, e.g., diazepam; monoamine oxidase(MAO) inhibitors, e.g., iproniazid, clorgyline, phenelzine,tranylcypromine, and isocarboxazid; biogenic amine uptake blockers,e.g., tricyclic antidepressants such as desipramine, imipramine andamitriptyline; atypical antidepressants such as mirtazapine, nefazodone,bupropion; serotonin reuptake inhibitors e.g., fluoxetine, venlafaxine,and duloxetine; antipsychotic drugs such as phenothiazine derivatives(e.g., chlorpromazine (thorazine) and trifluopromazine)), butyrophenones(e.g., haloperidol (Haldol)), thioxanthene derivatives (e.g.,chlorprothixene), S and dibenzodiazepines (e.g., clozapine);benzodiazepines; dopaminergic agonists and antagonists e.g., L-DOPA,cocaine, amphetamine, a-methyl-tyrosine, reserpine, tetrabenazine,benztropine, pargyline; noradrenergic agonists and antagonists e.g.,clonidine, phenoxybenzamine, phentolamine, tropolone. In anotherembodiment of the treatment methods, the compounds administered comprisecompounds, in particular drugs, reported to ameliorate or exacerbate thesymptoms of oxidative stress disorder. Such compounds include reduced ISglutathione (GSH), glutathione precursors, e.g., N-acetylcysteine;antioxidants, e.g., vitamins E and C, beta carotene and quinones;inhibitors of lipid membrane peroxidation, e.g., 21-aminosteroid U74006F(tirilazad mesylate), and lazaroids; antioxidants such as mazindol; 2cdizocilpine maleate; selegiline; sulfhydryls N-acetyleysteine andcysteamine; dimethylthiourea; EUK-8 a synthetic, low molecularsalen-manganese complex; synthetic manganese-based metalloproteinsuperoxide dismutase mimic, SC52608; free radical scavengers orsuppressors, e.g., pegorgotein, tocotrienol, tocopheral, MDL 74,18,LY231617, MCI-186, AVS (nicaraven), allopurinol, rifampicin, oxypurinol,hypochlorous acid or recombinant human Cu, Zn-SOD.

Co-administration of ketamine with a second therapeutic agent such asthose discussed above is provided in an amount effective to alleviateone or more symptoms of treatment-resistant depression.

The mild adverse effects of ketamine, e.g., dysphoria and/orhallucinations, sometimes called “ketamine dreams,” can occur uponadministration of a dose of greater than 50 mg of ketamine, and usuallyrequire doses greater than 100 mg of ketamine of total doseintranasally. One advantage of the present invention is that nasaldelivery of ketamine allows for control of the dose to a level effectivefor analgesia, but below the level that results in such dreams. However,it is possible that an individual may overdose, particularly in responseto an acute episode of depression. Thus, co-administration of a ketaminewith the additional exemplary antidepressant agents noted above may beindicated in order to achieve the beneficial anti-depressant effects ofketamine without the side effects of this agent.

In a preferred embodiment, a therapeutically effective amount of thesecond agent used for the treatment of depression herein is administeredin conjunction with ketamine. A therapeutically effective amount of thesecond agent is an amount effective to alleviate treatment-resistantdepression when co-administered with the ketamine.

As shown in the Examples below, patients treated with the intranasalketamine show remarkable recovery from depression. Such patients maythus end up using decreased amounts of the other antidepressantmedications.

As discussed above, the present invention is directed to various methodsand compositions for treating treatment-resistant depression comprisingintranasal administration of ketamine. In an alternative embodiment, thepresent invention contemplates intravenous administration of ketaminefor the treatment of treatment-resistant depression. Such treatment maybe administered alone or may be supplemented with other antidepressanttherapies as described herein.

IV administration of ketamine (0.5 mg/kg over 40 minutes) reportedimprovements in depression within 2 hours post-injection; and continuedfor up to 1 week. There were no serious adverse events caused by IVadministration. Any side effects observed were mild, e.g., euphoria,elevated BP, increased libido, perceptual disturbances, and furthermorethese effects abated within 80 min post-infusion. A chronic infusiondosing strategy has been previously described in two patients withdepression (Correll et al., Pain Medicine, 7: 92-95. 2006), beginningwith IV infusion at 0.1-0.2 mg/kg/hour (15-20 mg/hour). In these cases,dosing was maintained for 5 days, and the endpoint of titration waspsychotomimetic side effects. However, there is no report in theliterature of a tolerability threshold dose that is maintained for anadditional six to nine treatments.

The invention for the first time provides a method of treatingtreatment-resistant depression comprising intravenous administration ofketamine, wherein the administration is repeated multiple times within aspecific time period. For example, the administration is administered atleast twice, at least three times, at least four times, at least fivetime, at least six times, at least seven times, at least eight times, atleast nine times, or at least ten times over a period of two to threeweeks.

In another alternative embodiment, the administration comprisestransdermal administration. Such treatment may be administered alone ormay be supplemented with other antidepressant therapies as describedherein. Transdermal administration includes passive or activetransdermal or transcutaneous modalities, including, for example,patches and iontophoresis devices, as well as topical application ofpastes, salves, or ointments.

To date, there are only two published studies of transdermal ketamine,both for use in pain disorder (Vranken et al., Pain., 118:224-31, 2005,Azevedo et al., Anesth Anal., 91: 1479-82, 2000). Neither of thesestudies provides any teaching of the treatment of depression that isresistant to treatment. Vranken et al. studied the use of aniontophoretic patch (a mechanism of delivery in which the electricallycharged drug is transmitted by pulses of galvanic current) in 33 men andwomen with intractable central neuropathic pain. Vranken et al. chose touse an enantiomer of ketamine, S(+)-ketamine, a compound two times morepotent than racemic (which is a mixture of the S(+) and R(+))(Schuettler et al., Ketamine and its isomers, Textbook of IntravenousAnesthesia. Edited by White P F. Baltimore, Williams & Wilkins, 1997, pp171-88). Using a randomized, double-blind, placebo-controlled design,subjects were administered either a dose of 50 mg (n=11), 75 mg (n=11),or placebo (n=11), delivered transdermally over 24 hours for 7 days.Vranken et al. found that although there was no change among groups inpain intensity (measure by the Visual Analog Scale), subjects given doseof 75 mg showed significant improvement in pain disability, andsubjective physical and mental function. The reported side effects wereminimal, with no reports of dissociation or psychotic symptoms. Adverseevents included sedation (50 mg, n=3; placebo, n=1), dizziness (50 mg,n=1; placebo, n=3), nausea/vomiting (75 mg, n=1), confusion (50 mg,n=1), vivid dreams (placebo, n=1; 50 mg, n=1) headache (placebo, n=1),and erythema (placebo, n=2). Ketamine blood levels were not measured inthis study.

The second study is a randomized, double-blind, placebo-controlled trialusing racemic ketamine in a transdermal delivery system (Azevedo et al.,2003). A total of 49 women (ketamine, n=26, placebo, n=23) were studiedafter abdominal gynecological surgery in which lidocaine epiduralblockade was used. Postoperatively, 25 mg is delivered over 24 hrs indecaying quantities (hours 1-4: 1.25 mg/hour; hours 5-8: 0.5 mg/hour;hours 9-24: 0.4 mg/hour). The outcome measure was the time to firstrescue analgesic, which was prolonged for ketamine compared to placebo.The subjects reported no side effects from the ketamine, such as nauseaor vomiting, confusion, or hallucinations. There is no report of thetransdermal administration of ketamine for treating treatment-resistantdepression. Similarly, there is no report of transdermal administrationof ketamine for treating treatment-resistant depression, wherein theadministration is repeated multiple times within a specific time period.For example, the administration is administered at least twice, at leastthree times, at least four times, at least five time, at least sixtimes, at least seven times, at least eight times, at least nine times,or at least ten times over a period of two to three weeks.

Ketamine is formulated into pharmaceutical compositions comprising acarrier suitable for the desired delivery method. Exemplary carriersinclude, but are not limited to, any of a number of standardpharmaceutical carriers such as sterile phosphate buffered salinesolutions, bacteriostatic water, and the like. A variety of aqueouscarriers may be used, e.g., water, buffered water, 0.4% saline, 0.3%glycine and the like.

The compositions of the invention may be designed to be short-acting,fast-releasing, long-acting, or sustained-releasing as described herein.Thus, the pharmaceutical formulations may also be formulated forcontrolled release or for slow release.

Specific dosages may be adjusted depending on conditions of disease, theage, body weight, general health conditions, sex, and diet of thesubject, dose intervals, administration routes, excretion rate, andcombinations of drugs. Any of the above dosage forms containingeffective amounts are well within the bounds of routine experimentationand therefore, well within the scope of the instant invention.

The invention also provides a device for patient self-administration ofketamine, which device comprises a transdermal patch containing aketamine formulation and a pharmaceutically acceptable carrier, whereinthe device is formulated to disperse an amount of the ketamineformulation that contains a dose of ketamine effective to alleviatedepression.

Those of skill in the art are well aware of general technologies fortransdermal drug delivery or administration of a therapeutic agent tothe skin. Transdermal drug delivery offers controlled release of a drugto the patient and transdermal patches are user-friendly, convenient,painless, and offer multi-day dosing which usually results in improvedpatient compliance. In addition, this form of administration of ketaminein the present invention is a particularly useful alternative tointranasal delivery as it is less likely to lead to drug abuse ascompared to an intranasal delivery method. The methods of the inventionfor treating treatment-resistant patients with a transdermaladministration of ketamine can include administering ketamine to skin ofthe face, head or body. Such a ketamine composition can be administeredto the skin of the face, scalp, temporal region, arms, stomach, thighs,back, neck and the like. Suitable skin of the face includes skin of thechin, the upper lip, the lower lip, the forehead, the nose, the cheek,the skin around the eyes, the upper eyelid, the lower eyelid orcombinations thereof. Suitable skin of the scalp includes the front ofthe scalp, the scalp over the temporal region, the lateral part of thescalp, or combinations thereof. Suitable skin of the temporal regionincludes the temple and the scalp over the temporal region andcombinations thereof. The ketamine may be formulated into a bioadhesivepatch or a bioadhesive strip with an occlusive covering. Alternatively,the transdermal ketamine composition for administration to the skin canbe applied as a topical ointment, a topical gel, a lotion, a cream, asolution, a spray, a paint, a film, a foil, a cosmetic, to be applied tothe skin in a layer with or without an occlusive dressing.

In addition to transdermal patches, creams lotions and the like,intradermal administration of the ketamine composition also iscontemplated. Intradermal administration of a therapeutic agent isdefined as within or between the layers of skin. In contrast,subcutaneous administration is defined as beneath the initial layer ofskin and intravenous is a systemic administration into the bloodstream.Administration of therapeutic agents by intradermal, intravenous orsubcutaneous injection are common means of drug delivery by one skilledin the art.

Once a subject has been treated for depression using the methods of theinvention, he/she is monitored for depression symptoms by conventionalanalysis techniques as described above and such monitoring can be usedto adjust the dosage of therapy used.

Example 1

The following examples are included to demonstrate certain embodimentsof the invention. It should be appreciated by those of skill in the artthat the techniques disclosed in the examples which follow representtechniques discovered by the inventors to function well in the practiceof the invention, and thus are considered to constitute certain aspectsfor its practice. However, those of skill in the art should, in light ofthe present disclosure, appreciate that many changes can be made in thespecific embodiments which are disclosed and still obtain a like orsimilar result without departing from the spirit and scope of theinvention.

Methods

Men and women, ages 18 to 65 years, who were inpatients with a diagnosisof major depressive disorder recurrent without psychotic features asdiagnosed by means of the Structured Clinical Interview for Axis IDSM-IV Disorders—Patient Version 28 were eligible to participate.Subjects were required to have a score of ≧18 on the 21-item HamiltonDepression rating (HDRS) [29]) at screening and at start ofketamine/placebo infusion, and to have previously failed at least twoadequate antidepressant trials (adequacy of antidepressant trials weredetermined with the Antidepressant Treatment History Form [30]).

All subjects were in good physical health as determined by medicalhistory, physical exam, blood labs, electrocardiogram, chest x-ray,urinalysis and toxicology. Subjects were free of comorbid substanceabuse or dependence for at least 3 months and judged clinically not tobe a serious suicidal risk. Comorbid axis I anxiety disorder diagnoseswere permitted if they did not require current treatment.

Forty-two subjects were screened and twenty-four subjects were excludedas they did not meet inclusion/exclusion criteria (n=11) or refused toparticipate (n=13). After a 2 week drug-free period, 18 subjects withDSM-IV major depression were randomized to an intravenous infusion ofeither ketamine hydrochloride (0.5 mg/kg) or placebo (saline solution)given over 40 minutes with a Baxter infusion pump on 2 test days, a weekapart, in a double-blind, crossover study. Seventeen subjects receivedketamine and 14 received placebo. Four subjects did not receive placeboafter ketamine infusion because they maintained a response for more than7 days and one subject was discontinued from the study for medicalreasons after a placebo infusion.

Subjects were rated 60 minutes prior to the infusion and at 40, 80, 110,and 230 minutes as well as 1, 2, 3, and 7 days after the infusion. The21-item HDRS, Beck Depression Inventory Scale (BDI; [31]), BriefPsychiatric Rating Scale-positive symptoms (BPRS; [32]), Young ManiaRating Scale (YMRS; [33]), and the visual analogue scales score(VAS-depression; [34]). Raters, who trained together to establishreliability, performed patient ratings. High inter-rater reliability forthe HDRS (ICC=0.81) and the YMRS (ICC=0.91) were obtained. Subjects wererated by a separate set of raters to help maintain blind to the infusionprocedures and resulting side effects. The first set of ratersadministered the scales on the day of infusion (60 minutes prior to theinfusion and 40, 80, 110 post-infusion). From 230 minutes onwards (days1 through 7), a separate group of raters rated the subjects. Clinicalresponse was defined as a 50% or greater decrease in the HDRS ratingscale from baseline and remission as HDRS≦7 [35].

A full factorial, fixed effects linear mixed model with a compoundsymmetry covariance structure was used to examine the differencesbetween ketamine and placebo over 9 time points from baseline to 7 days.Restricted maximum likelihood estimation was used to estimate missingvalues. Significant effects were examined with simple effects tests. The21-item HDRS was the primary outcome measure. Scores from the BDI, BPRS,YMRS, and VAS were secondary outcome measures. Secondary analysisincluded examination of the individual items of the HDRS. Significancewas evaluated at α<0.05, two-tailed. Following Shapiro-Wilk's test andvisual examination of the data, no cells deviated substantially fromnormality.

Three sets of linear mixed models were run to fully understand theinfluence of the active treatment. One set of analysis included onlythose who completed both phases of the study (completers analysis).Subjects who did not receive both treatment conditions were not includedin this analysis. A second set included all available data (intent totreat analysis). Since ratings were made for each day regardless ofwhether the participants continued in the study, the placebo ratings forthe ketamine drop outs appeared to be much lower than would have beenexpected in an actual placebo phase. A third set of statistics wasperformed on the first test condition only. In this case the drug effectwas a between subjects factor instead of a within subjects factor.Secondary analysis on individual items was performed only withcompleters.

To evaluate the proportion of responders and remitters at each timepoint, a McNemar test was used at each time point for the completers andthe results were Bonferroni corrected for the number of time pointsexamined.

Carryover was examined using a linear mixed model with the samestructures as the primary analysis where drug was a within subjectsfactor, treatment order was a between subjects factor, and only thebaseline measure for each phase was used. The intent to treat sample wasused for this analysis since baseline data for both phases wasavailable.

Results

Subject's demographic and clinical characteristics are summarized inTable 1. There were 12 females, and 6 males, and the mean age was46.7±11.2. Sixty-one percent and 61% had a lifetime comorbid anxietydiagnosis, 39% a lifetime diagnosis of any substance abuse or dependenceand 28% a lifetime diagnosis of alcohol abuse or dependence. The meanlength of illness was 23.7 years±12.5, the mean duration of the currentdepressive episode was 33.6 months±37.4, and the mean number of lifetimeepisodes of depression was 6.6±4.7. The mean number of lifetimeantidepressant trials (not including augmentation trials) was 5.7±3.4and 4 subjects had previously received ECT. All subjects except for onehad failed an adequate antidepressant trial for the current majordepressive episode.

Using only those who completed both phases of the study, the linearmixed model with the HDRS showed significant main effects for drug(F=58.24, df=1,203, p<0.0001) and time (F=9.48, df=8,203, p<0.0001) andan interaction between drug and time (F=4.15, df=8,203, p<0.001). Simpleeffects tests indicated significant improvement on ketamine over placeboat 110 minutes through 7 days. The effect size for the drug differencewas very large (d=1.46, 95% C.I. 0.91-2.01) after 24 hours and moderateto large (d=0.68, 95% C.I. 0.13-1.23) after 1 week. The percent changein HDRS scores from baseline to day 1 for each subject is listed onTable 1. FIG. 2 shows the generalized least squares means and standarderrors for the completer analysis. The intent to treat analysis hadsimilar effects (drug: F=34.08, df=1,260, p<0.0001; time: F=8.92,df=8,257, p<0.0001; drug×time: F=5.29, df=8,257, p<0.0001). Notably,participants were better than placebo within 2 hours (110 minutes) andremained better through 7 days (FIG. 2).

Looking at possible carryover effects with the intent to treat sample, alinear mixed model looking at the baseline measures showed a significantmain effect for drug (F=6.25, df=1.16, p=0.02) and a significantinteraction (F=5.05, df=1.16, p=0.04), but no main effect for order(F=1.54, df=1.16, p=0.23). Participants who received placebo first hadsimilar baseline measures for the first and second phases (24.4±6.9 vs.24.9±6.8) (F=0.03, df=1.16, p=0.86), but those who received ketaminefirst had much lower baselines in the second phase (24.9±6.9 vs.17.2±6.9) (F=11.80, df=15, p=0.004).

To examine data relatively independent of carryover effects, only thefirst phase data was used in an additional analysis. Results weresimilar to those of the completers and intent to treat analysis. Therewere significant main effects for drug (F=10.44, df=1.16, p=0.005) andtime (F=8.25, df=8,126, p<0.0001) and a significant interaction betweendrug and time (F=4.66, df=1,126, p<0.0001). Scores were lower onketamine by 80 minutes and the difference remained significant throughthe seventh day.

Using the completers with the BDI, there were significant main effectsfor drug (F=50.57, df=1,200, p<0.0001) and time (F=5.82, df=8,200,p<0.0001) and a trend level interaction between drug and time (F=1.90,df=8,200, p=0.06). The patient ratings showed that ketamine seemed toimprove depression at 40 minutes through 7 days. Additionally, therewere significant changes in the VAS depression scores (drug: F=59.88,df=1,198, p<0.0001; time: F=4.70, df=8,198, p<0.0001; drug×time: F=1.92,df=8,198, p=0.058). Similar to BDI, ketamine improved mood at 40 minutesthrough 7 days.

On the individual HDRS symptoms, 7 of 20 symptoms had significant timeby drug interactions; loss of insight was not tested since none of theparticipants had this symptom. Depressed mood, guilt, work andinterests, and psychic anxiety improved significantly. The earliestimprovements were at 40 minutes for depressed mood and guilt.Depersonalization or derealization was worse from 40 to 110 minutes.Motor retardation and gastrointestinal symptoms were worse at 40minutes, but at day 1 motor retardation was better on ketamine than onplacebo. An additional 7 symptoms showed only a significant main effectfor drug; symptoms improved on ketamine for suicide, insomnia, generalsomatic symptoms, genital symptoms, and hypochondriasis. At baseline, nosymptoms were different between the ketamine and placebo phases.

FIG. 3 shows the proportion of responders (FIG. 3A) and remitters (FIG.3B) at each time point for the intent to treat sample. One day afterinfusion 12 of the 17 (71%) subjects treated with ketamine met responsecriteria as compared to 0 of 14 (0%) on placebo. Five of 17 (29%) onketamine met remission criteria one day after infusion, while none (0%)reached remission on placebo at the same time point. Six (35%) subjectsmaintained response to ketamine for at least 1 week; 2 of thesemaintained response at least 2 weeks. By contrast, no subject on placeboresponded at 1 or 7 days. For completers, McNemar tests showedsignificantly more responders to ketamine on day 1 and 2, but afterBonferroni correction, only day 1 was significant. The number ofremitters was not significant at any time point.

BPRS positive symptoms [35, 34] were worse on ketamine than placebo onlyat 40 minutes (drug: F=4.23, df=1,200, p=0.04; time: F=9.31, df=8,200,p<0.0001; drug×time: F=6.89, df=8,200, p<0.0001) (FIG. 2). Similarly,YMRS scores were worse (higher score) on ketamine than placebo at 40minutes only, but they were significantly better from days 1 to 2 (drug:F=3.08, df=1,201, p=0.08; time: F=3.54, df=8,201, p<0.001; drug×time:F=4.68, df=8,201, p<0.0001) (FIG. 2).

There was a trend for an inverse relationship between the percent changein HDRS at day 1 and the peak percent change in BPRS positive symptoms(r=−0.46, p=0.06). None of the other factors listed in table 1 predicteda response to ketamine.

Adverse Events:

Side effects occurring more commonly on ketamine than placebo wereperceptual disturbances, confusion, elevations in blood pressure,euphoria, dizziness, and increased libido. Side effects occurring morefrequently with placebo than ketamine were gastrointestinal distress,increased thirst, headache, metallic taste, and constipation. Themajority of these side effects ceased within 80 minutes after theinfusion. In no case did euphoria or derealization/depersonalizationpersist beyond 110 minutes (FIG. 2). No serious adverse events occurredduring the study.

Discussion

The present invention provides a robust, rapid (hours) and relativelysustained (1 week) response to a single-dose of the NMDA antagonistketamine. Improvement in mood ratings for the course of the week wasgreater with ketamine than placebo; this difference was statisticallysignificant for the 21-HDRS (from 110 minutes through 7 days) andself-rated BDI (from 40 minutes through 7 days). To our knowledge, therehas never been a report of any other drug or somatic treatment (i.e.,sleep deprivation, thyrotropin-releasing hormone, antidepressant,dexamethasone, or electroconvulsive therapy [ECT]) [36, 39, 40, 41, 42]that results in such a dramatic rapid and prolonged response with asingle administration. In reviews of antidepressant trials in majordepression response rates at week 8 were for bupropion 62%, SSRI 63%,and venlafaxine 65% [37, 38, 42]. In the present study involvingtreatment-resistant subjects, these response rates were obtained the dayafter the ketamine infusion.

In contrast to the dramatic effects observed in this study, a previouscontrolled study did not show the low- to moderate-affinitynon-competitive NMDA antagonist memantine, administered orally, to haveantidepressants effects [63, 38]. While it is likely that higheraffinity NMDA antagonists are necessary for antidepressant effects tooccur, it must be acknowledged that the intravenous administration mayalso be an important factor.

It is possible that higher affinity NMDA antagonists are necessary toinduce antidepressant effects. Ketamine in contrast to memantine has (a)higher affinity for the NMDA receptor, (b) much slower open channelblocking/unblocking kinetics, (c), a different type of channel closure(i.e., ‘trapping block’ as opposed to ‘partial trapping’ properties),[44, 63] and (d) different NMDA subunit selectivity [64, 65, 66]. Suchdifferences might explain the antidepressant properties observed withketamine in the present trial.

When comparing our results with the preliminary study by Berman et al.,[27] we confirmed the finding of rapid antidepressant response withketamine. The larger sample size of our study permitted us to obtainadditional information regarding the time of onset, course of responseand degree of improvement with ketamine. Compared to the previous study,we were able to (a) detect an earlier onset of antidepressant effect(110 minutes by objective ratings and 40 minutes by self-report,post-infusion vs. 230 minutes) after infusion; (b) find a more prolongedantidepressant effect of ketamine which remained significant up to 7days post-infusion (the previous study collected ratings only until day3); and (c) better characterize the magnitude of response and remissionobtained over the course of 7 days. The Berman et al., study groupreported that 4 of 8 patients obtained a 50% or greater decreases inHDRS during the 3-day follow-up period. In our study, we found 71%response and 29% remission rates on day 1 (FIGS. 2, 3) and 35% ofsubjects were able to maintain response for at least 1 week. Therelatively prolonged antidepressant effect that occurred with ketamine(−1 week) is remarkable considering its short half-life which isapproximately 2 hours for ketamine [67] and 5 hours for norketamine; thelatter metabolite is 7-10 times less potent than ketamine [68]. Bloodlevels of ketamine or its metabolites were not collected in this study.As a result, this study cannot rule out the possibility that differencesin drug metabolism may have contributed in part to the current findings.

It should be noted that although these results are provocative, they maynot be generalizable to all depressed populations. The subjects in thisstudy were a refractory subgroup who were relatively late in theircourse of illness (Table 1), and as such, their neurobiology andpharmacological responses may be different from those with a less severeor shorter course of illness.

Several factors need to be considered in interpreting these data.Although the sample size was relatively small, three different types ofanalysis showed significance of ketamine over placebo, and the effectsizes of this study were very large at day 1 and moderate to large atday 7. Consistent with all of the published randomizedplacebo-controlled studies with ketamine, we also found short-livedperceptual disturbances [26, 27, 44, 45, 46, 64]; it has to beacknowledged that such symptoms could have affected study blind. Hence,limitations in preserving study blind may have biased patient reportingby diminishing placebo effects, thereby potentially confounding results.One potential study design in future studies with ketamine might be toinclude an active comparator such as intravenous amphetamine (a dopamineagonist) which also produces psychotogenic effects [77].

However, the time of onset and course of antidepressant response(relatively prolonged) after receiving only one dose of ketamine wasnearly identical for each subject; this pattern suggests that there wasindeed, a true drug effect. The improvement associated with ketamineinfusion reflects a lessening of core symptoms of depression and isdisconnected from ketamine-induced euphoria and psychotomimeticsymptoms. In support, the antidepressant effect of ketamine becamesignificant in the HDRS scale at 110 minutes after a return of BPRSpositive and YMRS scores to baseline (FIG. 2). However, although BPRSpositive scores returned to baseline within 110 minutes, the change inBPRS positive symptoms from baseline to the 110 minute time pointtrended to predict a greater percent change (decrease) in HDRS scores atday 1. As a result, future research should explore a wider range ofketamine doses and rates of administration, and determine if thepresence or intensity of euphoric or psychomimetic effects are necessaryfor rapid antidepressant effects to occur. The dose of 0.5 mg/kg chosenfor the present study is reported to be sufficient to test the validityof the concept of the NMDA receptor antagonism with ketamine. The doseof ketamine used in our study was based on 1) in vitro data of NMDAblockade, 2) its mood enhancing effects in healthy volunteers and 3) itsantidepressant effects in a pilot study of patients with majordepression [27, 46].

While ketamine is believed to be relatively selective for NMDAreceptors, the possibility that these intriguing results are mediated byinteractions with other receptors cannot entirely be ruled out [65,69].However, ketamine binds to the NMDA receptor with an affinity that isseveral fold higher than that for other sites, [70, 71, 72, 73] andbehaviors induced by NMDA receptor antagonists are not blocked byopiate, cholinergic, or monoamine receptor antagonists [74], providingindirect evidence that ketamine's behavioral effects are mediated by itsinteraction with the phenylcyclidine (PCP) site. In vitro studies havefound that ketamine only reduces non-NMDA voltage-gated potassiumcurrents at much higher than reported in patients anesthetized withketamine [75]. This suggests that low doses of ketamine enhanceselectivity for the PCP site. Nevertheless, more selective NMDAantagonists will need to be tested in patients with major depression.Several NR2B subunit-selective antagonists are currently being developedfor ischemic brain injury [76].

In conclusion, the results of the present study support the hypothesisthat directly targeting the NMDA receptor complex may bring about rapidand relatively sustained antidepressant effects. This line of researchsuggests a novel avenue holds considerable promise for developing newtreatments for depression that have the potential to alleviate much ofthe morbidity and mortality associated with the delayed onset of actionof traditional antidepressants. Those of skill can now use the studiesdescribed herein to develop strategies for maintaining the rapidantidepressant response obtained with ketamine in long-term therapy.

Example 2 Repeated Administration of a Fixed Dose IV Ketamine

The following example describes a treatment strategy fortreatment-resistant depression involving the repeated administration ofketamine for rapid mood stabilization.

A fixed TV ketamine dose (0.5 mg/kg infusion over 40 minutes) isrepeated for up to six to nine sessions over a two to three week periodin hospital. The determination of the number of treatment sessions isbased on clinical response and tolerability. Standard pharmacotherapytreatments would be initiated in hospital such that once the finalketamine treatment session is completed; the patient has achieved atherapeutic dosage of an antidepressant for relapse prevention.

Example 3 Repeated Administration of a Continuation Dose of IV Ketamine

The following example describes another treatment strategy fortreatment-resistant depression involving the repeated administration ofa continuation dose of ketamine for rapid mood stabilization.

All patients would initiate IV ketamine at the dose of 0.5 mg/kg at arate of 1 mg/min, with continued titration over 40 minutes based ontolerability. At the first treatment, a tolerability threshold isdetermined using an empirical titration procedure based on the presenceof psychotic side effects. The individualized optimal tolerated dosewould serve as the continuation dosage for repeated treatments asdescribed in Example 2 above. For patients who respond to IV ketamine atthe 24 hour assessment, the continuation dose would be 20% reduced fromthe dose associated with psychotic side effects. If a patient did nothave any psychotic side effects and is a responder at 24 hours, then thestandard dose of 0.5 mg/kg is continued for the repeated dose phase.

Example 4 Transdermal Administration of Ketamine

The following example describes treatment strategies fortreatment-resistant depression involving transdermal administration ofketamine for rapid mood stabilization.

Another potential route of administration of ketamine is the use of atransdermal patch. Patients would be given a patch comprising areasonable starting dose for depression as described in Azevedo et al2003 (25 mg patch over 24 hours). For repeated dosing administration, apatch will be administered six-nine times over a two to three weekperiod. The determination of the number of treatment sessions is basedon clinical response and tolerability.

All of the above U.S. patents, U.S. patent application publications,U.S. patent applications, foreign patents, foreign patent applicationsand non patent publications referred to in this specification and/orlisted in the Application Data Sheet, are incorporated herein byreference, in their entirety.

From the foregoing it will be appreciated that, although specificembodiments of the invention have been described herein for purposes ofillustration, various modifications may be made without deviating fromthe spirit and scope of the invention.

TABLE 1 Demographic, and Clinical Characteristics Current Number ofFailed Length of Episode, previous medication and Number Age, yrs Genderillness, yrs mo episodes somatic treatments 1 43 F 24 4 10 SSRI (2);MAOI; AAP (2); BZD (3) 2 46 M 29 144 2 SSRI (3); SNRI; Bup; OAD (4) AAP;Lam; Sti; BZD 3 35 F 20 11 20 SSRI; Bup; TCA; OAD (2); AAP; Lam; BZD(3)4 43 F 24 24 4 SSRI (3); SNRI; Bup; OAD (2); Li; Lam; Sti (2) 5 45 F 279 1 SSRI (3); BZD 6 56 F 38 24 10 SSRI (3); Bup; TCA (2); VPA; BZD (2) 757 F 44 60 9 SSRI (3); Bup MAOI; OAD (2); AAP (3); Li; Lam; Sti; BZD(3); ECT 8 19 F 3 8 4 SSRI (3); Bup; Sti 9 48 F 33 60 9 SSRI (4); Bup;OAD; VPA; Sti; BZD l0 45 M 14 1 6 SSRI (4); TCA; OAD (3); Sti; BZD (3);ECT 11 28 M 16 17 4 SSRI (2); SNRI; TCA; OAD; AAP (2); Li; Lam; BZD (3)12 46 F 13 4 9 SSRI (2); Bup; TCA (2) 13 55 M 22 4 9 SSRI (2); Bup; AAP;Li; BZD; (2) 14 62 F 6 12 4 SSRI (3); OAD (2); BZD 15 60 F 47 55 3 SSRI(2); TCA; BZD (2) 16 59 M 7 84 3 SSRI (2) 17 50 M 31 60 3 SSRI (4); Bup;TCA (3); MAOI; OAD (7); VPA; Sti (3); BZD; AAP; Li; ECT 18 44 F 29 24 10SSRI; SNRI; TCA; OAD; AAP; Sti; ECT Group 46.7 ± 11.2 12 F/6 M 23.7 ±12.5 33.6 ± 37.4 6.6 ± 4.7 5.7 ± 3.4* 

Lifetime Peak change diagnosis of Lifetime in BPRS any substancediagnosis of positive % Change in HDRS abuse or alcohol abuse symptoms(day 1) Number dependence# or dependence on Ketamine Ketamine Placebo INo No +9 −90% N/A 2 No No +2 −85% −15% 3 Yes No +5 −78% N/A 4 No No +7−78% +11% 5 Yes Yes −1 −74% +14% 6 Yes Yes +7 −64% −18% 7 Yes Yes +3−61%  0% 8 No No 0 −57% −27% 9 Yes No +8 −55% N/A 10 Yes Yes +2 −54%+25% I1 No No −1 −50% −41% 12 No No +6 −50%  0% 13 No No −2  39% N/A 14No No +3 −39% −10% 15 No No +1 −36% −26% 16 No No +3 −29% −35% 17 No No+1 −17% −20% 18 Yes Yes N/A N/A  +8% Group 7 Yes/11 No 5 Yes/13 No +3.1± 3.4 −56.2 ± 20.4% −9.8 ± 20.1% Abbreviations: AAP, atypicalantipsychotic: BZD, benzodiazepine; Bup, buproprion; ECT;electroconvulsive therapy; HDRS, Hamilton depression rating scale; Lam,lamictal; Li, lithium; MAOI, monoamine oxidase inhibitor; OAD, otherantidepressants (e.g. nefazodone, trazodone, pramipexole, etc): SNRI,selective norepinephrine reuptake inhibitor; SSRI, selective serotoninreuptake inhibitor; TCA, tricyclic antidepressants; VPA, depakote; Sti,stimulant; #lifetime substance abuse/column also includes subjects withlifetime alcohol abuse/dependence; *number of antidepressant trials notincluding augmentation strategies;

 All subjects except for one had failed an adequate antidepressant trialfor the current depressive episode; “−” indicates a decrease in HDRSscores (improvement of depression) and “+” indicates an increase in HDRSscores (worsening of depression).

All of the compositions and/or methods disclosed and claimed herein canbe made and executed without undue experimentation in light of thepresent disclosure. While the compositions and methods of this inventionhave been described in terms of specific embodiments, it will beapparent to those of skill in the art that variations of thecompositions and/or methods and in the steps or in the sequence of stepsof the method described herein can be made without departing from theconcept, spirit and scope of the invention. More specifically, it willbe apparent that certain agents which are both chemically andphysiologically related may be substituted for the agents describedherein while the same or similar results are achieved. All such similarsubstitutes and modifications apparent to those skilled in the art aredeemed to be within the spirit, scope and concept of the invention asdefined by the appended claims.

The references cited herein throughout, to the extent that they provideexemplary procedural or other details supplementary to those set forthherein, are all specifically incorporated herein by reference. Atcertain points throughout the specification, references are referred tousing an number in square brackets. Those numbers correspond to thefollowing list of references, each of which is incorporated herein byreference:

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What is claimed is:
 1. A method of treating depression comprisingintranasally administering a dose of ketamine effective to alleviatedepression to a patient afflicted with depression that has not respondedto at least two adequate antidepressant treatments.
 2. The method ofclaim 1 wherein said dose is between 0.13 to 0.53 mg/kg/day.
 3. Themethod of claim 1, which comprises administration of multiple doses ofsaid ketamine.
 4. The method of claim 1, which comprises administrationof a single dose of said ketamine over a period of 7 days.
 5. The methodof claim 1, further comprising administering a pharmaceuticallyeffective dose of a second agent, wherein said second agent is anantidepressant agent.
 6. The method of claim 5 wherein saidantidepressant agent is selected from the group consisting of at leastone member of lithium, a pharmaceutical antidepressant, an herbalantidepressant, an anticonvulsant, a mood stabilizer, an antipsychoticagent, and a benzodiazepine.
 7. The method of claim 1 wherein thedepression comprises major depressive disorder.
 8. The method of claim 1wherein said effective dose is up to 250 mg/day.
 9. The method of claim1 wherein the patient has not responded to at least two adequateantidepressant trials in the current episode.
 10. The method of claim 9,which comprises administering multiple doses of said ketamine to thepatient.
 11. The method of claim 9, wherein said dose is between about0.1 mg/kg/day to about 3.0 mg/kg/day.
 12. The method of claim 1 whereinthe symptoms of said depression are alleviated within 2 hours ofadministering the ketamine.
 13. The method of claim 1 wherein thesymptoms of the depression are alleviated within one day ofadministering the ketamine.
 14. The method of claim 1 wherein at leastone of the adequate treatments is selected from the group consisting ofselective serotonin reuptake inhibitors, selective norepinephrinereuptake inhibitors, tricyclic antidepressants, monoamine oxidaseinhibitors and electroconvulsive therapy.
 15. A method for treatingdepression in a patient that has not responded to at least two adequateantidepressant treatments comprising intranasally administering a doseof ketamine effective to alleviate depression to the patient after theadequate antidepressant treatments.